2. Academic Validation
  3. Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects

Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects

  • J Med Chem. 2024 May 9;67(9):7603-7619. doi: 10.1021/acs.jmedchem.4c00442.
Jolien De Neve 1,  Khadija Elhabazi 2,  Simon Gonzalez 1,  Claire Herby 3,  Séverine Schneider 3,  Valérie Utard 2,  Rosine Fellmann-Clauss 2,  Nathalie Petit-Demouliere 2,  Sandra Lecat 2,  Mélanie Kremer 4,  Aurelia Ces 4,  François Daubeuf 5,  Charlotte Martin 1,  Steven Ballet 1,  Frédéric Bihel 3,  Frédéric Simonin 2
Affiliations

Affiliations

  • 1 Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
  • 2 Biotechnologie et Signalisation Cellulaire, UMR 7242, Centre National de la Recherche Scientifique, Université de Strasbourg, 67400 Illkirch, France.
  • 3 Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, UMR 7200, Centre National de la Recherche Scientifique, Université de Strasbourg, 67400 Illkirch, France.
  • 4 Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives (INCI), 67000 Strasbourg, France.
  • 5 Plateforme de Chimie Biologique Intégrative de Strasbourg, UAR 3286, Centre National de la Recherche Scientifique, Université de Strasbourg, 67400 Illkirch, France.
PMID: 38687204 DOI: 10.1021/acs.jmedchem.4c00442
Abstract

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains Opioid Receptor Agonist and Neuropeptide FF Receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid Peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.

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